Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
  • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new analgesic compounds prepared by the hydrolysis of N-acylated 4-hydroxyphenylamine derivatives, the synthesis of these compounds and pharmaceutical compositions containing them. These compounds surprisingly possess high analgesic activity with little hepatotoxic effect, making them more useful than conventional non-steroidal anti- inflammatory drugs (NSAIDs) in the treatment of chronic pain.
• NSAIDs non-steroidal anti- inflammatory drugs
• Analgesics such as acetaminophen and other NSAIDs, have been used for some time for the treatment of pain.
• morbidity associated with the hepatotoxic activity means that due care must be exercised when administering these drugs .
• Acetaminophen has a toxic metabolite, N-acetyl-benzoquinoneimine (NAPQI) , which depletes hepatic and renal glutathione, a cytoprotective endogenous metabolite (Mason & Fischer, 1986; Mitchell et al . , 1983). Hepatic and renal toxicity with acetaminophen can occur at doses only 4- to 8-fold higher than the maximum recommended analgesic dose (Neuberger et al . , 1980). Pharmaceutical combinations that contain acetaminophen and a centrally acting analgesic may be even more dangerous than acetaminophen alone .
• NAPQI N-acetyl-benzoquinoneimine
• SCP series N-acylated 4-hydroxyphenylamine derivatives linked via an alkylene bridge to the nitrogen atom of a l,2-benzisothiazol-3 (2H) -one 1,1-dioxide group
• SCP series N-acylated 4-hydroxyphenylamine derivatives linked via an alkylene bridge to the nitrogen atom of a l,2-benzisothiazol-3 (2H) -one 1,1-dioxide group
• n is a number from 1 to 5.
• N- acylated-4-hydroxyphenylamine derivatives linked via an alkylene bridge to the nitrogen atom of a 2-sulfamoyl benzoic acid group surprisingly possess high analgesic activity and little hepatotoxic effect .
• Te present invention relates to new analgesic compounds prepared by the hydrolysis of N-acylated 4-hydroxyphenylamine derivatives.
• the new analgesic compounds have the general formula II:
• n is a number between 1 and 5.
• the present invention also includes the formation of pharmaceutically acceptable, stable salts of SCP-M series compounds with metals or amines.
• metals used in cations are alkali metals such as Na or K and alkaline-earth metals such as Mg and Ca.
• amines include N,N- dibenzylethylendiamine, chloroprocaine, choline, diethanolamine, ethylendiamine, N-methylglucamine and procaine .
• the present invention includes pharmaceutical compositions comprising a compound from the SCP-M series in combination with opioid and non-opioid analgesics.
• Figure 1 is the effect of SCP-M1 on CFA-induced thermal hyperalgesia shown as a percentage of pre-drug baseline.
• Figure 2 is a comparison of the effects of SCP-M1 and acetaminophen on pro-apoptotic FAS-ligand up-regulation and CAR activation.
• the compounds of the present invention may be administered alone or mixed with a pharmaceutical vehicle selected in accordance with the administration route and standard pharmaceutical practice, e.g. orally, rectally, topically, parenterally, and intrathecally. They may be administered orally, either in the form of tablets containing excipients such as starch or lactose, or in capsules, either alone or mixed with excipients, or in the form of syrups or suspensions containing coloring or flavoring agents. They may also be injected parenterally, for example intramuscularly, intravenously or subcutaneously.
• parenteral administration they can preferably be used in the form of a sterile aqueous solution, which can contain other solutes, such as, for example, any salt or glucose in order to make the solution isotonic.
• Intrathecal administration can be delivered by either spinal tap injection or by catheterization.
• Intrathecal drug administration can avoid the inactivation of some drugs when taken orally as well and the systemic effects of oral or intravenous administration.
• intrathecal administration permits use of an effective dose that is only a fraction of the effective dose required by oral or parenteral administration.
• the intrathecal space is generally wide enough to accommodate a small catheter, thereby enabling chronic drug delivery systems.
• Intrathecal treatment of chronic pain is primarily performed by use of an intrathecal pump.
• the pump may be surgically placed under the skin of the patient's abdomen.
• One end of a catheter is connected to the pump, and the other end of the catheter is threaded into a CSF filled subarachnoid or intrathecal space in the patient's spinal cord.
• the implanted pump can be programmed for continuous or intermittent infusion of the drug through the intrathecally located catheter.
• the compounds of the present invention may be administered for the treatment of pain, for example orally, either covered in gelatin capsules or compressed in lozenges.
• said compounds may be mixed with excipients and used in the form of lozenges, tablets, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like.
• compositions and preparations obtained according to the present invention are prepared in such a way that each oral dosage unit can contain between about 0.1 and about 1000 mg of the active compound.
• the active compounds of this invention should be incorporated in a solution or suspension.
• These preparations could contain at least 0.1% of the active compound, but preferably varies between 0.5% and 50% approximately of the weight of the preparation.
• the amount of active compound in such compositions should be that which is necessary for obtaining the corresponding dosage.
• compositions and preparations obtained according to the present invention are prepared in such a way that each parenteral dosage unit can contain between 0.5 and 1000 mg of the active compound.
• intramuscular administration may be given in a single dose or divided into up to three doses
• intravenous administration can include a drip device for giving the dose by venoclysis.
• Parenteral administration of the preparation may be performed by means of ampoules, disposable syringes or multiple-dose vials made of glass or plastic.
• the active compounds of this invention may be employed with or without diluents or may be reconstituted with autologous spinal fluid.
• Intrathecal administrations could contain at least 0.1 ⁇ g of the active compound, but can contain between 0.1 and 100 ⁇ g of the active compound.
• the present invention also includes pharmaceutical compositions comprising a compound from the SCP-M series in combination with opioid and non-opioid analgesics.
• the drugs that comprise the group known as the opioid analgesics include among others the phenanthrene alkaloids of opium, comprising morphine, codeine, and thebaine. While thebaine produces no analgesia, it is an important intermediate in the production of semisynthetic opioids .
• agents with structures and function related to morphine include: (1) the morphine analogs, such as hydromorphone, oxymorphone, hydrocodone, and oxycodone; (2) Diels-Alder adducts, such as etorphine and buprenorphine; (3) the morphinan derivatives, such as dextromethorphan and butorphanol; (4) the benzomorphan derivatives, such as phenazocine, pentazocine and cyclazocine; (5) the piperidine derivatives, such as meperidine and anileridine; and (6) open chain analgesics (methadone type compounds), such as methadone and propoxyphene .
• the morphine analogs such as hydromorphone, oxymorphone, hydrocodone, and oxycodone
• Diels-Alder adducts such as etorphine and buprenorphine
• the morphinan derivatives such as dextromethorphan and butorphan
• the drugs that comprise the group known as the non-opioid analgesics include: (1) N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan and ketamine and other antagonists that suppress central sensitization by competing for any of the binding site subcategories associated with the NMDA receptor, e.g., the glycine binding site, the phenylcyclidine (PCP) binding site, etc., as well as the NMDA channel; (2) alpha 2 adrenoreceptor agonists, such as clonidine, metomidine, detomidine, dexmetomidine, dexmedetomidine and xylazine, that reduce the release of norepinephrine; (3) other agents, such as tramadol, often mistakenly referred to as an opioid, that produce analgesia by their inhibitory actions on monoamine re-uptake rather than by agonist effect; (4) non-steroidal anti-inflammatory drugs such as
• the pharmaceutical combinations of the present invention comprise an opioid or a non-opiod analgesic in an intimate admixture with an analgesic from the SCP-M series along with a pharmaceutically acceptable carrier prepared according to conventional pharmaceutical techniques.
• Pharmaceutically acceptable carriers include solid or liquid fillers, diluents, and encapsulating substances .
• the amount of the carrier employed in conjunction with the combination is sufficient to provide a practical quantity of material per unit dose of analgesic.
• Pharmaceutically acceptable carriers for oral administration include, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water.
• Pharmaceutically acceptable carriers for parenteral administration include isotonic saline, propylene glycol, ethyl oleate, pyrrolidone, aqueous ethanol, sesame oil, corn oil, and combinations thereof.
• Various oral dosages forms can be employed, including solid forms such as tablets, capsules, granules and bulk powders.
• Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
• Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, and reconstituted solutions and/or suspensions.
• Pharmaceutically effective combinations can contain between 0.1 and 1000 mg of an analgesic from the SCP-M series.
• the preferred pharmaceutically effective combinations contain between 400 and 1000 mg of an analgesic from the SCP-M series.
• the pharmaceutically effective amounts of the opioid and non-opioid analgesics in combination with analgesics in the SCP-M series are similar to the corresponding combinations of opioid and non- opioid analgesics with acetaminophen.
• BIOLOGICAL RESULTS To determine whether the SCP-M series has analgesic activity, its effect on Complete Freund's Adjuvant (CFA) -induced thermal hyperalgesia was accessed. Under halothane anesthesia, male CD-I mice were injected with 0.1 ml of CFA (Calbiochem, USA) to the glabrous surface of one hind paw.
• CFA Complete Freund's Adjuvant
• CFA When injected into the footpad, CFA produces localized inflammation and hyperalgesia that appears within two hours and is present for 7 to 10 days (Iadorola, et al . , 1988).
• each mouse received by oral gavage 2.5 mmol/kg of SCP-M1 or vehicle.
• the latency to withdraw the paw from a thermal stimulus was measured using an analgesiometer (IITC Life Sciences, Inc., Woodland Hills, CA) according to the technique of Hargreaves, et al .
• the stimulus intensity was set to produce baseline latencies of about 10-15 seconds, and a 20 second maximum latency was used.
• Thermal hyperalgesia was measured before drug administration (pre-drug baseline) , and again at 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 5 hour, and 6 hour after drug administration.
• SCP-Ml The effects of SCP-Ml on CFA-induced thermal hyperalgesia are shown as a percentage of pre-drug baseline in Figure 1.
• the SCP-M series displays little or no hepatotoxic effect.
• the hepatotoxic effects of SCP-Ml were evaluated in human hepatocytes (HEPG-2) and in human primary cultures of normal liver cells. Acetaminophen, a known hepatotoxic analgesic, was used as a positive control. Phase contrast, microscopy, Trypan blue exclusion, Hoechst staining, and FAS-ligand and CAR (constitutive androstane receptor) induction were used as criteria.
• HEPG-2 human hepatocytes
• Hoechst staining indicated that SCP-Ml was practically ineffective in inducing cell death, whereas acetaminophen induced severe apoptotic cell death.
• analysis of the hepatotoxic effects of SCP-Ml and acetaminophen measured by the Trypan blue exclusion and Hoechst staining showed that the hepatotoxic effects exerted by these compounds were very much comparable to those in HEPG-2 cells, enhanced apoptosis was caused by acetaminophen but not SCP-Ml.
• HEPG-2 cells were grown and maintained in EMEM medium containing NEAA (nonessential amino acids) , supplemented with 10% fetal bovine serum (FBS) , and incubated at 37 °C with a constant supply of 5% C0 2 .
• Primary human liver cells were grown in HCM medium (Walkersville, MD) , and maintained in HMM medium (Walkersville, MD) at 37 °C with 5% C0 2 .
• HEPG2 and primary hepatocytes growing in 6- and 24-well plates were held 6-8 hr in serum-free medium (EMEM, 0.5% FBS for HEPG2 and HMM [Clonetics, Walkersville, MD] for primary hepatocytes) before the addition of analgesics.
• the serum-starved cells were treated with SCP-Ml or acetaminophen for 6-8 hr at 37 °C. Hoechst staining was employed for detection of apoptosis.
• Spent medium was removed from the experimentally treated cells, which were washed with 2 ml PBS (room temperature) .
• CAR constitutive androstane receptor
• the SCP-M series compounds may be prepared according to the following reaction scheme:

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